Candidate: The candidate is a physician trained and board certified in Internal Medicine, Infectious Diseases and Pulmonary and Critical Care Medicine who is currently a Brookdale Leadership in Aging Fellow and Ph.D. candidate in the Investigative Medicine Program at the Yale School of Medicine. He has a track record in geriatric medicine and research. He attended medical school at the Alexander von Humboldt University in Berlin, Germany and earned a Masters in Public Health from the Johns Hopkins School of Public Health. He has persistently shown leadership qualities in the field of aging, starting with his training in geriatric medicine, early research on health care policies for the elderly and more recently in the basic science arena dedicated to vaccine research for the elderly. During his clinical training, he became aware of the complex challenges in the care of patients in the geriatric age group. As a result, he decided to focus his research on understanding age associated changes in human immune responses, with an emphasis on innate immunity. His long-term career goal is to obtain a tenure-track position at an academic institution with a majority of his time dedicated to basic scientific investigation. The applicant ill achieve this objective by carrying out the proposed research plan under the supervision of two highly qualified mentors, and with guidance by a Mentorship Advisory Committee composed of leaders in immunology, geriatrics, and clinical epidemiology and biostatistics. The applicant proposes a focused program of didactic courses and participation in research seminars that will complement his completed graduate curriculum. Ultimately, when the candidate establishes his own independent research laboratory in a tenure-track faculty appointment, he will integrate his clinical and research training to pursue translational research on aging and innate immune responses in the lung. Environment: The environment at Yale is ideal for pursuing human translational research. The candidate and his mentors have a longstanding collaboration with the Program on Aging and Pepper Center at Yale, which provide recruitment, informatics and biostatistical support for human studies, and have longstanding relationships with leaders in the Department of Immunobiology at Yale, who are located in the same building. Research: The candidate's published work recently demonstrated a generalized defect in Toll-like Receptor (TLR) function in dendritic cell (DC) populations from older (over 65 years), compared to young (21-30 years) individuals. Here, we focus on understanding the basis for the age-associated decrease in TLR1 surface expression observed in older individuals, which appears to arise from post-translational mechanisms. We will employ an array of state of the art cell biology techniques to evaluate age-associated changes in the kinetics and trafficking of TLR1 including the contribution of TLR chaperone proteins such as PRAT4a, whose expression we have found to be decreased in cells from older individuals. Taken together, the proposed research, career development and mentoring activities will facilitate the candidate's training as a productive physician-scientist. PUBLIC HEALTH RELEVANCE: Aging is associated with a progressive decline in immune function (immunosenescence) resulting in increased susceptibility to viral and bacterial infections and decreased response to vaccines. While it is likely that comorbid conditions contribute to the observed increase in mortality, it is clear that impaired host defenses associated with aging also contribute to increased morbidity and mortality. Our research focuses on defects of the innate immunity arm in older adults, and we hope that, ultimately, our work will help explain the deterioration of immunity seen in older adults, and aid in the rational development of novel treatments and vaccines geared specifically towards older adults.